Non-donating nsaids adsorbed into carrier particles

ABSTRACT

The present invention relates to porous particles comprising one or more NO-donating Non Steroidal Antiinflammatory Compound(s) optionally mixed with one or more surfactant(s) and to new solid drug delivery composition comprising said particles optionally in combination with a second active drug. Futhermore, the invention relates to processes for producing said porous particles and solid drug delivery composition as well as the use of said composition in the manufacturing of a medicament. The No-donating NSAID may be in oily or melted form.

FIELD OF INVENTION

The present invention relates to porous particles comprising one or moreNO-donating Non Steroidal Antiinflammatory Compound(s) (NSAID(s)),optionally mixed with one or more surfactant(s) and to a new solid drugdelivery composition comprising said particles optionally in combinationwith a second active drug.

Futhermore, the invention relates to processes for producing said porousparticles and solid drug delivery composition as well as the use of saidcomposition in the manufacturing of a medicament.

BACKGROUND OF THE INVENTION

Non-steroidal anti-inflammatory drugs, commonly and hereafterabbreviated as NSAIDs, are well-known drugs for the treatment of painand inflammation. One of the major drawbacks with NSAIDs is that theyhave severe gastrointestinal side-effects. Patients undergoing treatmentwith NSAIDs for a longer period of time, such as naproxen, oftenexperience problems with stomach gastrointestinal side-effects.

Nitrogen oxide donating NSAID drugs (in the following NO-donatingNSAIDs), have been found to have an improved side-effect profile, seee.g. WO 94/04484, WO 94/12463, WO 95/09831 and WO 95/30641.

NO-donating NSAIDs are lipophilic drugs with poor aqueous solubility. Abiopharmaceutical problem with these drugs is that their absorption fromthe gastrointestinal tract (GIT) may be dissolution rate limited,resulting in poor bioavailibility upon oral administration.

Many of the NO-donating NSAIDs are obtained as such, in the form of anoily compound. Therefore, the conventional methods for formulating thesecompounds such as tabletting are not applicable for these compounds.Oily active drugs have generally been produced and put on the market insoft gelatine capsules. NO-donating NSAIDs in oily form cannot, in itspure form, be compressed into a conventional tablet.

One advantageous solution to the problem in handling oily substances andto obtain a dosage form for oral administration is forming a SelfEmulsifying Drug Delivery System, commonly known as SEDDS, e.g. asdescribed in WO 01/66087. More particularly, the SEDDS is apharmaceutical composition suitable for oral administration, in the formof an emulsion pre-concentrate, comprising one or more NO-donatingNSAID(s); one or more surfactants; and optionally an oil or semi-solidfat. The composition forms in-situ an oil-in-water emulsion upon contactwith aqueous media such as gastrointestinal fluids. The pre-concentrateemulsion is usually filled into conventional capsules.

The self-emulsifying process of a SEDDS formulation depends mainly onthe characteristics of the oil(s)/surfactant(s) mixture and the amountof surfactant. The polarity of the oil affects the solubility propertiesand the self-emulsification ability of the oil. In the literature it issuggested to use a surfactant that achieves a hydrophilicity of theemulsion that is thought to be necessary for immediate/rapid formationof an oil-in-water emulsion. SEDDS formulations of NO-donating NSAID(s),containing a surfactant(s) form an emulsion. This depends on theproperties of the NO-donating NSAID combined with the properties of thesurfactant(s). Aulton, M. E. Pharmaceutics, The science of dosage formdesign, p. 291, (1988), Gershanik, T.; Benita, S., Eur. J. Pharm.Biopharm., 50, 179 (2000), Bachynsky, M. O.; Shah N. H.; Patel, C. I.;Malick, A. W., Compound. Dev. Ind. Pharm., 23(8), 809 (1997), Pouton, C.W., Adv. Compound Deliv.

Rev., 25, 47 (1997), Shah N. H.; Carvajal, M. T.; Patel, C. I.; Infeld,M. H.; Malick, A. W., Int. J. Pharm., 106, 15 (1994), Costantinides, P.P., Pharm. Res., 12(11), 1561 (1995).

Emulsion or preconcentrates are not the preferred formulations inpharmaceutical industry. One drawback may for example be the stabilityof such formulations. Tablets and capsules are often preferred in viewof large scale manufacturing of drug delivery compositions.

Tabletted compositions comprising an oily, sticky active agent and amethod for producing such compositions are described in WO 99/27912 andWO 99/27913. These documents describe absorption of the oily stickycomponent into a porous carrier. However, compositions comprisingNO-donating NSAIDs are not mentioned or proposed in any of thesedocuments and no compressed tablets comprising NO-donating NSAIDs arehitherto known.

One of the unique features of NO-donating NSAIDs is that many of thesedrugs are oils or thermosoftening semisolids, which are practicallyinsoluble in water. With high-dose NO-donating NSAIDs, e.g. when thedose is above about 350 mg, it is difficult to formulate a tablet ofreasonable size of the large amount of oil or semisolid.

In the attempts to make conventional tablets comprising NO-donatingNSAIDs, such as NO-donating naproxen, which is a so-called high dosedrug, the result has been a too large tablet. The patient compliancewill be influenced by a tablet of unacceptable size.

The object of the present invention is to provide solid drug deliverycompositions comprising NO-donating NSAID(s) such as tablets andcapsules of acceptable size to the patients.

DETAILED DESCRIPTION OF THE INVENTION

NO-donating NSAIDs are lipophilic drugs with poor aqueous solubility.They can be classified into class 2 according to the BiopharmaceuticalClassification System proposed by Amidon et al. (Pharm. Res. 12 (1995)pp. 413-420). Compounds of this class are characterised by their lowaqueous solubility but reasonably well permeability. A biopharmaceuticalproblem with these drugs is that their absorption from thegastrointestinal tract (GIT) may be dissolution rate limited, resultingin poor bioavailibility upon oral administration. One object of theinvention is to provide an oral formulation with satisfactorybioavailability.

Active Drug

The wording “NSAID” is defined as a non-steroidal anti-inflammatorydrug, i.e. any drug having an anti-inflammatory effect, but which drugdoes not belong to the drug class “steroids”. A person skilled in theart will recognise a drug that falls under the definition NSAID.Examples of specific NSAIDs are naproxen, diclofenac, aceclofenac,indomethacine, ketorolac, sulindac, meloxicam, piroxicam, tenoxicam,ibuprofen, ketoprofen, naproxen, azapropazon, nabumetone, carprofen,tiaprofenic acid, suprofen, indoprofen, etodolac, fenoprofen, fenbufen,flurbiprofen, bermoprofen, pirazolac, zaltoprofen, nabumetone,bromfenac, ampiroxicam and lomoxicam. This list should however not beconsidered as exhaustive in any way.

The wording “NO-donating NSAID” is contemplated to include anynon-steroidal anti-inflammatory drug (NSAID), a salt or an enantiomerthereof, which has the capability to release nitrogen oxide.

NO-donating NSAIDs that may be used in accordance with the presentinvention, are drugs of the formula I

wherein:

-   X is a spacer, i.e. a drug forming a bridge between the nitrogen    oxide donating group and the NSAID; and-   M is selected from anyone of    or a salt or an enantiomer thereof.

In one embodiment of the invention, the spacer X is selected from alinear, branched or cyclic alkylene group —(CH₂)—_(n) wherein n is aninteger from 2 to 10; and —(CH₂)_(m)—O—(CH₂)_(p)— wherein m and p areintegers from 2 to 10; and —CH₂-pC₆H₄—CH₂— wherein p is an integer offrom 2 to 10.

The spacer X may also contain a sulfur or heterocycle group.

The NO-donating NSAIDs contemplated as active drug(s) as well asprocesses for their preparation are disclosed in WO 94/04484, WO94/12463, WO 95/09831 and WO 95/30641, which are hereby incorporated byreference. These documents also describe that the NO-donating NSA/Dshave an improved side-effect profile.

Further examples of active drug(s) that may be used in the compositionof the present invention are compounds disclosed in WO 96/32946, WO00/25776, EP 1126838, EP 821589, WO 02/60378, FR 2735366, FR 2737662, CN1144092, WO 01/12584, WO 98/25918, WO 00/51988 and WO 00/06585, whichare hereby incorporated by reference.

Specific NO-donating NSAIDs useful in accordance with the presentinvention are

One embodiment of the invention relates to solid drug deliverycomposition comprising porous particles comprising one or moreNO-donating NSA/D(s) wherein the NO-donating NSAID(s) is selected froman NO-donating naproxen, an NO-donating diclofenac and an NO-donatingketoprofen.

In another embodiment of the invention the NO-donating naproxen is4-(nitrooxy)-butyl(S)-2-(9-methoxy-2-naphtyl)-propanoate (Compound offormula Ia).

In a further embodiment of the invention the NO-donating diclofenac is2-[(2,6-dichlorophenyl)amino]benzeneacetic acid 4-(nitrooxy)-butyl ester(Compound of formula Ig).

In yet a further embodiment of the invention the NO-donating diclofenacis 2-[2-(nitrooxy)ethoxy]ethyl{2-[(2,6-dichlorophenyl)amino]phenyl}acetate (Compound of formula IL).

In another embodiment of the invention the NO-donating ketoprofen is2-(3-benzoyl-phenyl)-propionic acid 3-nitrooxy-propyl ester or2-(3-benzoyl-phenyl)-propionic acid 4-nitrooxymethyl-benzyl ester(Compound of formula Ic and Compound of formula If, respectively).

The Drug Delivery Composition

A new way of formulating the NO-donating NSAID(s) is to absorb it intoporous carriers. Useful carriers for the NO-donating NSA/D(s) arecarriers having properties such as a high oil-absorbing capacity, sothat the drug easily absorbs into the carrier. Also, the carrier shouldhave a satisfying liquid-holding ability, the volume of the active drugmust be kept to guarantee the dose administered.

The invention relates to a solid drug delivery composition comprisingone or more NO-donating Non Steroidal Antiinflammatory Compound(s)(NO-donating NSAID(s)) absorbed into porous particles.

The invention further relates to a solid drug delivery compositionwherein one or more NO-donating NSAID(s) in oily form is absorbed intoporous particles.

The invention also relates to a solid drug delivery composition whereinone or more NO-donating NSAID(s) in melted form is absorbed into porousparticles.

The material of the porous particles used for absorbing the NO-donatingNSAID(s) and for carrying the active drug in a drug delivery compositionmay be selected from materials such as, for example, calcium silicate,e.g. known under the trade name Florite™, dibasic calciumphosphateanhydrous, e.g.: known under trade name Fujicalin™, magnesiumaluminometasilicate, e.g. known under trade name Neusilin™ andmicrocrystalline cellulose.

One embodiment of the invention relates to solid drug deliverycomposition according to the present invention wherein the porousparticles are selected from the group consisting of dibasic calciumphosphate anhydrous, microcrystalline cellulose and pregelatinisedstarch or a mixture thereof.

The porous carriers exemplified above are free-flowing, which isadvantageous during handling and preparation. The porous particle,comprising one or more NO-donating NSAID(s), may be used for directcompression into a multiple unit tableted delivery composition. Anotherexample of a suitable dosage form is a capsule filled with the porousparticles comprising one or more NO-donating NSAID(s). A further exampleof a suitable dosage form is a sachet comprising said the porousparticles comprising one or more NO-donating NSAID(s).

The porous particle material used as carrier shall have a particle sizebetween 50 and 500 μm, particularly a size between 100 and 150 μm.

Thus 95% of the particles used in the composition of the presentinvention shall have a size in the ranges mentioned above.

The liquid absorption capacity of the particles is suitably between 0.70and 4.0 ml/g.

The pore size of the porous particles should be between 10 and 1000 Å,particularly between 20 and 750 Å, and most suitably between 50 and 500Å.

Thus 95% of the particles used in the composition of the presentinvention shall have a pore size in the ranges mentioned above.

The invention relates to compositions wherein the NO-donating NSAID(s)have been absorbed into porous particles. Examples of suitableNO-donating NSAIDs are NO-donating naproxen, NO-donating diclofenac andNO-donating ketoprofen (according to Formula Ia, Ic, If, Ig and IL). Theinvention is not in any way restricted to compositions comprising theseactive drugs.

The NO-donating NSAIDs may be finely dispersed and absorbed into theporous particles either as the sole drug; as SEDDs; as a water-in-oilemulsion; as an oil-in-water emulsion; or as a dissolved or meltedcrystalline drug.

The releasing rate of the active drug from the composition may beinfluenced by the presence or absence of one or more surfactant(s). Ithas been shown that the release characteristics can be changed by addingone or more surfactant(s). The rate of release may be increased if asuitable surfactant is present together with the active drug into theporous particle.

The invention relates to a solid drug delivery composition comprisingporous particles wherein one or more NO-donating NSAID(s) is absorbedtogether with one or more surfactant(s) into the porous particles.

Further, to control the release from the tablet, a SEDDS-mixture of theNO-donating drug may be absorbed into the porous particles.

Further, the present invention relates to a solid drug deliverycomposition comprising a combination of

-   a) porous particles comprising an NO-donating NSAID and one or more    surfactant(s) and-   b) porous particles comprising an NO-donating NSAID without    surfactant.

Such a solid drug delivery composition will give a more advanced releaseprofile, for example a first rapid onset by the release from the porousparticles comprising the NO-donating NSAID with one or moresurfactant(s) followed by a delayed release from the porous particlescomprising the NO-donating NSA/D alone.

The NO-donating NSA/D(s) used for such a combination may be the same ordifferent.

The wording “surfactant” is defined as surface-active amphiphilic drugssuch as block co-polymers. suitable surfactants are non-ionicsurfactants, for example those containing polyethylene glycol (PEG)chains, particularly block co-polymers such as poloxamers. Oneembodiment of the invention relates to polyoxyethylene polyoxybutyleneblock copolymer.

Examples of suitable poloxamers that may be used in the composition ofthe present invention are Poloxamer 407 (Pluronic F127™); Poloxamer 401(Pluronic L121™); Poloxamer 237 (Pluronic F87™); Poloxamer 338 (PluronicF108™); Poloxamer 331 (Pluronic L101™); Poloxamer 231 (Pluronic L81™);tetrafunctional polyoxyethylene polyoxypropylene block copolymer ofethylene diamine, e.g. known as Poloxamine 908 (Tetronic 908™);Poloxamine 1307 (Tetronic 1307™); Poloxamine 1107; polyoxyethylenepolyoxybutylene block copolymer, e.g. known as Polyglycol BM45™. Thislist of poloxamers serves as examples of surfactants that may be used inthe present invention, and should not in any way be considered asexhaustive or limiting the invention.

All surfactants described above are commercially available from, e.g.BASF, Dow Chemicals, and Gattefossé. The total amount of surfactant(s)may be within a range from 12.5 to 6000 mg, particularly from 100 to 500mg.

The ratio NO-donating NSAID(s):surfactant(s) may vary from 1:0.1 to 1:10(w/w), particularly from 1:0.3 to 1:3 (w/w).

Furhter, the solid drug delivery composition of the present inventionmay comprise a combination of one or more NO-donating NSA/D(s),optionally with one or more surfactant(s) and one or more other activedrugs.

Preparation of the Drug Delivery Composition

The incorporation of the NO-donating NSAID(s), into the porous particlesmay be accomplished by conventional known methods.

Without Surfactant

The porous particles comprising one or more NO-donating NSAID(s) may beprepared in different ways, for example by mixing the NO-donatingNSAID(s) with the porous particles directly, e.g. in a mortar.

Alternatively, the drug may be dissolved in a suitable solvent, such asone or more alcohol(s) for example, ethanol. The porous particles maythan be added after which the active drug will be absorbed. Thesolvent(s) is then evaporated and the particles are collected.Furthermore, the NO-donating NSA/D(s) may be melted before mixing withthe porous particles.

The invention relates to a process for producing the porous particlescomprising one or more NO-donating NSAID(s) comprising mixing theNO-donating NSAID(s), optionally in oily or melted form, with porousparticles.

One embodiment of the invention relates to a process for producing theporous particles comprising one or more NO-donating NSAID(s) comprising:

-   a) dissolving the NO-donating NSAID(s) in one or more alcohol(s),-   b) adding the porous particles during stirring,-   c) evaporating the added alcohol(s),-   d) recovering the porous particles comprising the NO-donating    NSAID(s), with a) and b) in optional order.

Another embodiment of the invention relates to a process for producingthe porous particles comprising one or more NO-donating NSAID(s)comprising:

-   a) melting the NO-donating NSAID(s),-   b) adding the porous particles,-   c) stirring the obtained mixture,-   d) recovering the porous particles comprising the NO-donating    NSAID(s), with a) and b) in optional order.

The NO-donating NSAID(s) used in these processes may be the same ordifferent.

With Sufactant

One or more surfactant(s) is added to the active drug before adding theporous particles.

The components may also be melted before mixing to get a homogeneousmixture of the two components before the addition of the porousparticles.

The NO-donating NSAID(s) may be mixed with one or more liquidsurfactant(s), and then absorbed into porous particles.

One embodiment of the present invention relates to a process forproducing porous particles comprising one or more NO-donating NSAID(s)and one or more surfactant(s) comprising:

-   a) mixing NO-donating NSAID(s) and the surfactant(s),-   b) adding the porous particles,-   c) stirring the obtained mixture,-   d) recovering the porous particles comprising NO-donating NSAID(s)    and the surfactant(s),    with a) and b) in optional order.

Another embodiment of the present invention relates to a process forproducing the porous particles comprising one or more NO-donatingNSAID(s) and the surfactant(s) comprising:

-   a) melting NO-donating NSAID(s) and the surfactant(s),-   b) adding the porous particles,-   c) stirring the obtained mixture,-   d) recovering the porous particles comprising NO-donating NSAID(s)    and the surfactant(s),    with a) and b) in optional order.

The NO-donating NSAID(s) used in these processes may be the same ordifferent.

Spheronization

The porous particles according to the invention may also be produced byway of spheronization. Speronization may be performed in anyconventional way known to the man in the art. PharmaceuticalPelletization Technology“ ”, Ed.: Isaac Ghebre-Sellasie, 1989, Marceland Dekker, Inc.

One embodiment of the present invention relates to a process forproducing the porous particles comprising one or more NO-donatingNSAID(s) comprising:

-   a) mixing the NO-donating NSAID(s) and the porous excipient,-   b) adding water, stepwise, continuously, in one portion,-   c) extruding the obtained mixture into particles,-   d) spheronising the obtained particles,-   e) drying the obtained mixture,-   f) recovering the porous particles comprising the NO-donating    NSAID(s).

The NO-donating NSAID(s) in step a) may optionally be pre-heated.

The NO-donating NSAID(s) used in this processes may be the same ordifferent.

The term ‘extruding’ shall mean forcing out, pushing out or expulsing.

The porous particles comprising the NO-donating NSAID(s) with or withoutsurfactant(s), may be mixed with pharmaceutical acceptable excipientssuch as fillers, binders, disintegrants and/or pharmaceuticallyadditives, carriers and diluents, before formulation in a suitable drugdelivery composition.

The porous particles comprising the NO-donating NSAID(s) with or withoutsurfactant(s), may also be used as such.

Optionally, the prepared porous particles comprising the NO-donatingNSAID(s) with or without surfactant(s), may be mixed with a secondactive drug, for example, enteric coating layered pellets comprising aproton pump inhibitor.

Such a composition may be formulated by mixing the porous particlescomprising the NO-donating NSAID(s) with or without surfactant(s), andthe second active drug with pharmaceutical acceptable excipients such asfillers, binders, carriers, diluents, disintegrants and/orpharmaceutically additives followed by formulation of the obtainedmixture into a suitable drug delivery composition.

Examples of suitable drug delivery composition are capsules and tablets.Tablets may be obtained by direct compressed.

Example of suitable excipients, but not limited thereto, aremicrocrystalline cellulose and polyvinyl pyrrolidone, hydroxypropylmethylcellulose (HPMC), lactose, sodium carboxymethylcelulolose (NaCMC).

The particles, capsules and tablets may be coated by ways well known inthe art.

The filling into capsules, compressing to tablets and coating shouldpreferably be performed in such a manner that does not substantiallyinfluence the release characteristics of the solid drug deliverycomposition after administration.

The prepared particles, capsules and tablets may be coated by aconventional film coat or a sugar coat, to obtain an improvedappeareance. Suitable layering material for the film coat but notlimited thereto, are derivatives of cellulose, such ashydroxypropylmethylcellulose, methylcellulose or ethylcellulose andacrylate-based polymers.

Sugar coating involves successive application of sucrose based solutionsto the particles, capsules or tablets.

One embodiment of the present invention relates to a solid drug deliverycomposition wherein the porous particles are mixed with pharmaceuticallyacceptable excipients and compressed into a tablet.

A further embodiment of the present invention relates to a solid drugdelivery composition wherein the porous particles are filled into acapsule.

Another embodiment of the present invention relates to a solid drugdelivery composition wherein the capsules and tablets are coated.

If a fast release of the active drug is desired in the small intestine,the loaded porous particles may be enteric coated.

Some of the NO-donating NSAIDs may be high dose drugs. One embodiment ofthe invention relates to a divisable dosage form, for example, adivisable tablet.

The total amount of NO-donating NSAID(s) used in the composition of theinvention is particularly in the range from 50 to 1500 mg per unit dose.The amount of a low dose NO-donating NSAID may be between 75 and 350 mgper unit dose. The amount of a high dose NO-donating NSA/D may bebetween between 350 and 1500 mg per unit dose.

The term “unit dose” is defined as the amount of active drugadministered in one tablet, in one single capsule or a sachet.

Combinations

It is well known that patient compliance is an important factor inreceiving an optimal result in medical treatments. An improved patient'scompliance is obtained by administering different drugs in one dosageform.

One embodiment of the invention relates to a solid drug deliverycomposition comprising two or more different active drugs combined inone composition. Examples of a solid drug delivery composition in theform of a multiple unit tablet are shown. The solid drug deliverycomposition comprising such a combination may simplify the dosingregimen and improve patient compliance.

One embodiment of the invention relates to a mixture of porous particlescomprising different NO-donating NSAIDs, with or without surfactant(s).For example, a combination of an NO-donating diclofenac and anNO-donating naproxen. This composition has an advanced release profilewhereby the fast immediate release of NO-donating diclofenac is combinedwith the good maintenance of NO-donating naproxen.

Another embodiment of the invention relates to a combination of

-   a) porous particles comprising one or more NO-donating NSA/D(s),    with or without surfactant(s) and-   b) one or more other active drugs.

Each active drug may have a special requirement for being administered.

The NO-donating NSAID(s) may for example be combined with active drugssuch as, anti-ulcer drugs. The porous particles comprising one or moreNO-donating NSAID(s) according to the present invention may be combinedwith enteric coated pellets comprising a proton pump inhibitor, such asomeprazole. The H⁺, K⁺-ATPase inhibitors are one preferred group ofdrugs for combining with NO-donating NSAID(s). Examples of isspecifically preferred drugs of H⁺, K⁺-ATPase inhibitors are acidsusceptible proton pump inhibitors, for example drugs of the generalformula II below. Although NO-donating NSAID(s) have an improvedside-effect profile with respect to NSAID(s), the administration ofNO-donating NSAID(s) together with a proton pump inhibitor may be asuccessful combination of drugs.

Compounds of formula II:

wherein:

-   Het₁ is-   Het₂ is    and wherein-   N in the benzimidazole moiety means that one of the carbon atoms    substituted by R₆-R₉ optionally may be exchanged for a nitrogen atom    without any substituents;-   R₁, R₂ and R₃ are the same or different and selected from hydrogen,    alkyl, alkoxy optionally substituted by fluorine, alkylthio,    alkoxyalkoxy, dialkylamino, piperidino, morpholino, halogen, phenyl    and phenylalkoxy;-   R₄ and R₅ are the same or different and selected from hydrogen,    alkyl and aralkyl;-   R₆ is hydrogen, halogen, trifluoromethyl, alkyl and alkoxy;-   R₆-R₉ are the same or different and selected from hydrogen, alkyl,    alkoxy, halogen, haloalkoxy, alkylcarbonyl, alkoxycarbonyl, oxazolyl    and trifluoroalkyl, or adjacent groups R₆-R₉ form ring structures,    which may be further substituted;-   R₁₀ is hydrogen or forms an alkylene chain together with R₃ and-   R₁₁ and R₁₂ are the same or different and selected from hydrogen,    halogen, alkyl and the alkyl groups.

The alkyl groups, alkoxy groups and moieties thereof, included in thesubstituents R₁-R₁₂ above may be branced or straight C₁-C₉-chains orcomprise cyclic alkyl groups, such as cyclo-alkyl-alkyl.

Examples of proton pump inhibitors are omeprazole, esomeprazole,lansoprazole, pantoprazole or rabeprazole, leminoprazole or mixturesthereof. These examples are not in any way a restriction ofpossibilities.

The acid susceptible proton pump inhibitors used in the dosage forms ofthe invention may be used in their neutral form or in the form of analkaline salt, such as for instance the Mg²⁺, Ca²⁺, Na⁺, K⁺ or Li⁺salts, particularly the Mg²⁺ salts. Further, where applicable, the drugslisted above may be used in racemic form or in the form of thesubstantially pure enantiomer thereof, or alkaline salts of the singleenantiomers.

Suitable proton pump inhibitors are for example disclosed inEP-A1-0005129, EP-A1-174 726, EP-A1-166 287, GB 2 163 747 and WO90/06925, WO 91/19711, WO 91/19712, and further especially suitabledrugs are described in WO 95/01977 (magnesium omeprazole) and WO94/27988 (the single enantiomers of omeprazole salts).

The proton pump inhibitors used in a combination in accordance with thepresent invention are particularly provided as enteric coating layeredpellets comprising the acid susceptible proton pump inhibitor. For thecomposition of the enteric coating layered pellets and its preparation,reference is made to WO 96/01623, which is hereby incorporated byreference.

One embodiment of the invention relates to a solid drug deliverycomposition wherein the porous particles comprising a NO-donating NSAID,optionally mixed with one or more surfactant(s), are mixed together withenteric coated pellets comprising a H⁺, K⁺-ATPase inhibitor.

Another embodiment of the invention relates to a solid drug deliverycomposition wherein the porous particles comprising an NO-donatingnaproxen, an NO-donating diclofenac, an NO-donating ketoprofen or anNO-donating ketorolac, optionally mixed with one or more surfactant(s),are mixed together with enteric coated pellets comprising omeprazole,esomeprazole, lansoprazole, pantoprazole or rabeprazole, leminoprazoleor a pharmaceutical acceptable salt thereof.

Suitable combinations in accordance with the present invention are forinstance an NO-donating NSAID of the formula Ia (NO-donating naproxen)and omeprazole or an alkaline salt of omeprazole, (S)-omeprazole; anNO-donating NSAID of the formula Ig (NO-donating-diclofenac) andomeprazole or an alkaline salt of omeprazole, (S)-omeprazole or anNO-donating NSAID of the formula IL (NO-donating diclofenac) andomeprazole or an alkaline salt of omeprazole, (S)-omeprazole.

Preparation of the Combination

One embodiment of the invention relates to a solid drug deliverycomposition comprising a proton pump inhibitor (in the form of aracemat, an alkaline salt or one of its single enantiomers) and one ormore NO-donating NSAIDs characterized in that the individually entericcoating layered units containing the proton pump inhibitor andoptionally containing alkaline reacting substances, are mixed with theporous particles comprising the absorbed NO-donating NSAID(s) preparedaccording to the present invention and pharmaceutically acceptableexcipients. The NO-donating NSAID(s) and excipient may also be in theform of granules. The dry mixture of enteric coating layered unitscomprising the proton pump inhibitor and the porous particles comprisingthe NO-donating NSAID(s) are formulated into a suitable dosage deliverycomposition such as a tablet, capsule or a sachet.

With the expression “individual units” is meant small beads, porousparticles, granules or pellets, in the following referred to as pelletsof the acid susceptible proton pump inhibitor.

When the solid drug delivery composition is a tablet, care should betaken not to affect the acid resistance of the enteric coating layeredpellets comprising the acid susceptible proton pump inhibitorsignificantly during the compaction process. In other words themechanical properties, such as the flexibility and hardness as well asthe thickness of the enteric coating layers(s), should be secured sothat the requirements on enteric coated articles as specified in theUnited States Pharmacopeia are accomplished with, i.e. the acidresistances should not decrease more than 10% during the compression ofthe pellets into tablets.

The acid resistance is defined as the amount of proton pump inhibitor intablets or pellets after being exposed to simulated gastric fluid USP,or the 0.1 M HCL (aq) relative to that of unexposed tablets and pellets,respectively. In test the individual tablets or pellets are exposed tosimulated gastric fluid of a temperature of 37° C. The tabletsdisintegrate rapidly and release the enteric coating layered pellets tothe medium. After two hours the enteric coating layered pellets areremoved and analyzed for content of the proton pump inhibitor using HighPerformance Liquid Chromatography (HPLC).

Use

The invention relates to the use of the solid drug delivery compositionfor the manufacture of a medicament for treating pain.

The invention further relates to the use of the solid drug deliverycomposition according for the manufacture of a medicament for treatinginflammation.

The invention relates further to a method for the treatment of paincomprising oral administration to a patient suffering therefrom a solidcompound delivery composition according to the present invention.

The invention relates even further to a method for the treatment ofinflammation comprising oral administration to a patient sufferingtherefrom a solid compound delivery composition according to the presentinvention.

EXAMPLES

The invention will now be described in more detail by the followingexamples, which are not to be construed as limiting the invention in anyway.

The examples show the processes for producing the solid drug deliverycomposition comprising porous particles comprising one or moreNO-donating NSAID(s) and a solid drug delivery composition comprisingporous particles comprising one or more NO-donating NSAID(s), optionallymixed with one or more surfactant(s). Also, an example showing a soliddrug delivery composition of a combination of an NO-donating NSAID andthe proton pump inhibitor omeprazole is presented.

The following porous materials were used in the examples: calciumsilicate, dibasic calciumphosphate anhydrous (Fujicalin™) and magnesiumaluminometasilicate (Neusilin™).

The following surfactants were used in the examples: Poloxamer 237(Pluronic F87™) and Poloxamer 338 (Pluronic F108™).

The following microcrystalline cellulose was used in the examples:Avicel™ pH 102.

Characteristics of the Porous Particles (95%) Pore size Surface areaParticle diameter Fujicalin ™ 7.5 nm 33 m²/g 40-150 μm Neusilin ™ — 110m²/g 40-80 μmExperiments of Compositions Comprising One NO-Donating NSAID

Free-flowing powders comprising porous particles comprising the activedrug were made by mixing the active drug with porous particles asdescribed below.

I. Compound of Formula Ia

The mixtures A to F were mixed with a pestle in a mortar at 60° C.

A) Compound of Formula Ia/Neusilin™ 1/1

-   12.50 g Compound of formula Ia-   12.50 g Neusilin™    B) Compound of Formula Ia/Fujicalin™ 1/2-   8.33 g Compound of formula Ia-   16.67 g Neusilin™    C) Compound of Formula Ia/Neusilin™ 2/1-   16.67 g Compound of formula Ia-   8.33 g Neusilin™    D) Compound of Formula Ia/Fujicalin™ 1/1.5-   10 g Compound of formula Ia-   15 g Fujicalin™    E) Compound of Formula Ia/Fujicalin™ 1/1.25-   11 g Compound of formula Ia-   13.75 g Fujicalin™    F) Compound of Formula Ia/Calcuim silikate 1/4-   5 g Compound of formula Ia-   20 g Calcuim silicate

The above mentioned mixtures A to F were sieved through a 0.5 mm sieve,and mixed with tablet excipients according to the excipient mixture 1and 2 as described below. The compositions were compressed into tablets,weighing 1200 mg, using a tablet machine rigged with 18 mm oval punches.

Excipient Mixture 1

-   48.30 g Avicel™ pH 102-   1.65 g Polyvinyl pyrrolidone, cross-linked-   0.15 g Sodium stearyl fumarate    Excipient Mixture 2-   48.30 g Avicel™ pH 102-   1.65 g Polyvinyl pyrrolidone, cross-linked    Composition 1:    Tablets, 640 mg Compound of Formula Ia-   10 g Compound of formula Ia/Neusilin™ 2/1 (C)-   2.5 g Excipient mixture 1.    Composition 2:    Tablets, 320 mg Compound of Formula Ia-   10 g Compound of formula Ia/Fujicalin™ 1/2 (B)-   2.5 g Excipient mixture 1    Composition 3:    Tablets, 200 mg Compound of Formula Ia-   6 g Compound of formula Ia/Fujicalin 1/2 (B)-   6 g Excipient mixture 1    Composition 4:    Tablets, 300 mg Compound of Formula Ia-   6 g Compound of formula Ia/Neusilin™ 1/1 (A)-   6 g Excipient mixture 1    Composition 5:    Tablets, 200 mg Compound of Formula Ia-   6 g Compound of formula Ia/Neusilin™ 1/2 (B)-   6 g Excipient mixture 1    Composition 6:    Tablets, 240 mg Compound of Formula Ia-   6 g Compound of formula Ia/Fujicalin™ 1/1.5 (D)-   6 g Excipient mixture 2    Composition 7:    Tablets, 267 mg Compound of Formula Ia-   6 g Compound of formula Ia/Fujicalin™ 1/1.25 (E)-   6 g Excipient mixture 2    Composition 8:    Tablets, 375 mg Compound of Formula Ia-   9.38 g Compound of formula Ia/Fujicalin™ 1/1.5 (D)-   2.62 g Excipient mixture 2    Composition 9:    Tablets, 375 mg Compound of Formula Ia-   8.44 g Compound of formula Ia/Fujicalin™ 1/1.25 (E)-   3.56 g Excipient mixture 2    Composition 10:    Tablets, 120 mg Compound of Formula Ia-   10 g Compound of formula Ia/Calcuim silicate 1/4 (F)-   10 g Excipient mixture 1    Results—Compositions 1 to 10

The dissolution rate was determined by using a thermostated beaker witha magnetic stirrer (150 rpm). The dissolution medium had a temperatureof 37° C. The media used was phosphate buffer pH=6.8, containing 8.8mg/litre of CTAB. The increase in absorbance corresponded to the releaseof Compound of Formula Ia. Composition 1. Tablet, 640 mg of Compound ofFormula Ia Time % Released 5 min 1 10 min 4.9 15 min 12.1 30 min 24.3 60min 38.1

Composition 2. Tablet, 320 mg of Compound of Formula Ia Time % Released5 min 15 10 min 30 15 min 40 30 min 50 60 min 60

Composition 3. Tablet, 200 mg of Compound of Formula Ia Time % Released5 min 26.5 10 min 51.4 15 min 61.6 30 min 83 60 min 91

Composition 4. Tablet, 300 mg of Compound of Formula Ia Time % Released5 min 2 10 min 5.5 15 min 8.3 30 min 17.2 60 min 28.5

Composition 5. Tablet, 200 mg of Compound of Formula Ia, Time % Released5 min 1 10 min 1 15 min 2.3 30 min 5.7 60 min 9.1

Composition 6. Tablet, 240 mg of Compound of Formula Ia Time % Released5 min 31.5 10 min 51.9 15 min 63.1 30 min 83 60 min 98.2

Composition 7. Tablet, 267 mg of Compound of Formula Ia Time % Released5 min 26.7 10 min 43.6 15 min 56.5 30 min 78.9 60 min 97.8

Composition 8. Tablet, 375 mg of Compound of Formula Ia Time % Released5 min 19 10 min 30.5 15 min 37.5 30 min 52 60 min 59

Composition 9. Tablet, 375 mg of Compound of Formula Ia Time % Released5 min 18.9 10 min 31.5 15 min 40.5 30 min 51.6 60 min 62

Composition 10. Tablet, 120 mg of Compound of Formula Ia Time % Released10 min 23 20 min 37 30 min 47 40 min 55 60 min 67Experiments of Compositions Comprising a Spheronised NO-Donating NSAIDG. Spheronised Compound of Formula Ia

-   200 g Compound of formula Ia-   600 g Avicel™ pH 102-   100+150+150+50 g water

The Avicel™ pH 102 was put in an intense mixer, the Compound of formulaIa was preheated to 45° C., and added to the Avicel™ pH 102 in theintensive mixer. After 3 minutes of mixing, water was added in portionsstated above, under continuously mixing. Then the wet mass was extrudedthrough a screen, diameter=1.0 mm. The extruded mass was thenspheronised in a 0.325 mm spheroniser. The spheronised mass was thendried in a fluid bed at 45° C. for 5 minutes.

After the Compound of formula Ia had been spheronised and dried, anexcipient mixture 2 was added.

Composition 11:

-   10 g Spheronised Compound of formula Ia (G)-   10 g Excipient mixture 2

The tablet blend was sieved and then mixed in a Turbula for two minutes.

The obtained mixture was compressed into tablets, weighing 800 mg(corresponding to 92 mg of active), using a tablet machine rigged with18 mm oval punches.

Result—Composition 11

Dissolution tests were made using a thermostated beaker with a magneticstirrer (300 rpm).

The media used was phosphate buffer pH=6.8, containing 8.8 mg/litre ofCTAB. The increase in absorbance corresponded to the release of Compoundof formula Ia. Composition 11. Tablet, 92 mg of Compound of Formula IaTime % Released 5 min 5 10 min 23 15 min 30 30 min 46 60 min 67Experiments of Compositions Comprising One NO-Donating NSAID with One orMore Surfactant(s)1. Compound of Formula Ia

A mixture of Compound of formula Ia and one or more surfactant(s) wasprepared by melting and mixing the surfactant(s) and the active drug at60° C.

A free-flowing powder comprising Compound of formula Ia was made byadding the mixture to porous particles and mixing the components with apestle in a mortar at 60° C.

H. Compound of Formula Ia/Pluronic F87™ 1/0.3

-   4 g Compound of formula Ia-   1.2 g Pluronic F87™    I. (Compound of Formula Ia/Pluronic F87™ 1/0.3)/Fujicalin™ 1/4-   2 g Compound of formula Ia/Pluronic F87™ (H)-   8 g Fujicalin™

The above mentioned mixtures H and I were sieved through a 0.5 mm sieveand mixed with excipients according to excipient mixture 2 as describedbelow.

The compositions were compressed into tablets, weighing 1200 mg, using atablet machine rigged with 18 mm oval punches.

Composition 12:

Tablets, 92 mg Compound of Formula Ia

-   5 g (Compound of formula Ia/Pluronic F87™ 1/0.3)/Fujicalin™ 1/4 (I)-   5 g Excipient mixture 2    Results—Composition 12

The dissolution rate was detemined in a thermostated beaker with amagentic stirrer (150 rpm). The media used was phosphate buffer pH-=6.8,containing 8.8 mg/litre of CTAB. The increase in absorbance correspondedto the release of Compound of formula Ia. Composition 12. Tablet, 92 mgof Compound of formula Ia Time % Released 5 min 80 10 min 96 15 min 9930 min 100 60 min 1002. Compound of Formula IL

Compound of formula IL was melted and thereafter mixed with the porousparticles. After the hot melt had been absorbed into the porousparticles, the excipient mixture 2 was added.

J. Compound of Formula IL/Fujicalin™ 1/2

-   2.5 g Compound of formula IL-   5 g Fujicalin™    Composition 13:    Tablets, 100 mg of Compound of Formula IL-   6 g Compound of formula IL Fujicalin™ (J)-   6 g Excipient mixture 2

The tablet blend was sieved and then mixed in a Turbula for two minutes.

The obtained mixture was compressed into tablets, weighing 600 mg(corresponding to 100 mg of Compound of formula IL), using a tabletmachine rigged with 18 mm oval punches.

Result—Composition 13

Dissolution tests were made using a USP paddle bath (USP dissolutiontest No. 2) operating at 50 rpm. The media used was phosphate bufferpH=6.8, containing 8.8 mg/litre of CTAB. The increase in absorbancecorresponded to the release of Compound of formula IL. Composition 13.Tablet, 100 mg of Compound of formula IL Time % Released 5 min 21 10 min33 15 min 40 30 min 56 60 min 70K. (Compound of Formula IL/Pluronic F108™ 1/0.3)/Fujicalin™ 1/2

-   3.0 g Compound of formula IL-   0.90 g Pluronic F108™-   7.80 g Fujicalin™

The active drug and the surfactants were melted together and thereaftermixed with the porous particles. After the hot melt (containing both theactive drug and surfactants) had been absorbed into the porousparticles, the excipient mixture 2 was added.

Composition 14:

Tablets, 100 mg of Compound of Formula IL

-   7.80 g (Compound of formula IL Pluronic F108™ 1/0.3)/Fujicalin™ 1/2    (K)-   7.80 g Excipient mixture 2

The tablet blend was sieved and then mixed in a Turbula for two minutes.

The obtained mixture was compressed into tablets, weighing 780 mg(corresponding to 100 mg of Compound of formula IL), using a tabletmachine rigged with 18 mm oval punches.

Result—Composition 14

Dissolution tests were made using a thermostated beaker with a magneticstirrer (300 rpm).

The media used was phosphate buffer pH=6.8, containing 8.8 mg/litre ofCTAB. The increase in absorbance corresponded to the release of Compoundof formula IL. Composition 14. Tablet, 100 mg of Compound of formula ILTime % Released 5 min 18 10 min 31 15 min 40 30 min 73 60 min 1003. Compound of Formula IcL. Compound of Formula Ic/Fujicalin™ 1/2

-   2.5 g Compound of formula Ic-   5 g Fujicalin™

The Compound of formula Ic was mixed with the porous particles. AfterCompound of formula Ic had been absorbed into the porous particles, theexcipients mixture 2 was added.

Composition 15:

Tablets, 100 mg of Compound of Formula Ic

-   6 g Compound of formula Ic/Fujicalin™ (L)-   6 g Excipient mixture 2

The tablet blend was sieved and then mixed in a Turbula for two minutes.

The obtained mixture was compressed into tablets, weighing 600 mg(corresponding to 100 mg of Compound of formula Ic), using a tabletmachine rigged with 18 mm oval punches.

Result—Composition 15

Dissolution tests were made using a thermostated beaker with a magneticstirrer (300 rpm). The media used was phosphate buffer pH=6.8,containing 8.8 mg/litre of CTAB. The increase in absorbance correspondedto the release of Compound of formula Ic. Composition 15. Tablet, 100 mgof Compound of formula Ic Time % Released 5 min 13 10 min 22 15 min 2930 min 35 60 min 39M. (Compound of Formula Ic/Pluronic F108™ 1/0.3)/Fujicalin™ 1/2

-   3.0 g Compound of formula Ic-   0.90 g Pluronic F108™-   7.80 g Fujicalin™

The active drug and surfactants were melted and mixed together andthereafter added to the porous particles. After the hot melt (containingboth drug and surfactants) had been absorbed into the porous particles,the excipients mixture 2 was added.

Composition 16:

Tablets, 100 mg of Compound of Formula Ic

-   7.80 g (Compound of formula Ic/Pluronic F108™ 1/0.3)/Fujicalin™ (M)-   7.80 g Excipient mixture 2

The tablet blend was sieved and then mixed in a Turbula for two minutes.

The obtained mixture was compressed into tablets, weighing 780 mg(corresponding to 100 mg of Compound of formula Ic), using a tabletmachine rigged with 18 mm oval punches.

Result—Composition 16

Dissolution tests were made using a thermostated beaker with a magneticstirrer (300 rpm). The media used was phosphate buffer pH=6.8,containing 8.8 mg/litre of CTAB. The increase in absorbance correspondedto the release of Compound of formula Ic. Composition 16. Tablet, 100 mgof Compound of formula Ic Time % Released 5 min 21 10 min 24 15 min 2930 min 36 60 min 394. Compound of Formula IfN. Compound of Formula If/Fujicalin™ 1/2

-   2.5 g Compound of formula If-   5 g Fujicalin™

The active drug (an oil) was mixed with the porous particles. After theactive had been absorbed into the porous particles, the excipientsmixture 2 was added.

Composition 17:

Tablets, 100 mg of Compound of Formula If

-   6 g Compound of formula If/Fujicalin™ (N)-   6 g Excipient mixture 2

The tablet blend was sieved and then mixed in a Turbula for two minutes.

The obtained mixture was compressed into tablets, weighing 600 mg(corresponding to 100 mg of Compound of formula If), using a tabletmachine rigged with 18 mm oval punches.

Result—Composition 17

Dissolution tests were made using a thermostated beaker with a magneticstirrer (300 rpm). The media used was phosphate buffer pH=6.8,containing 8.8 mg/litre of CTAB. The increase in absorbance correspondedto the release of Compound of formula If. Composition 17. Tablet, 100 mgof Compound of formula If Time % Released 5 min 15 10 min 22 15 min 2530 min 30 60 min 40O. (Compound of Formula If/Pluronic F108™ 1/0.3)/Fujicalin™ 1/2

-   3.0 g Compound of formula If-   0.90 g Pluronic F108™-   7.80 g Fujicalin™

The Compound of formula If and surfactant were melted together andthereafter mixed with the porous particles. After the hot melt(containing both drug and surfactant) had been absorbed into the porousparticles, the excipient mixture 2 was added.

Composition 18:

Tablets, 100 mg of Compound of Formula If

-   7.80 g (Compound of formula If/Pluronic F108™ 1/0.3)/Fujicalin™ (O)-   7.80 g Excipient mixture 2

The tablet blend was sieved and then mixed in a Turbula for two minutes.

The obtained mixture was compressed into tablets, weighing 780 mg(corresponding to 100 mg of Compound of formula If), using a tabletmachine rigged with 18 mm oval punches.

Result—Composition 18

Dissolution tests were made using a thermostated beaker with a magneticstirrer (300 rpm).

The media used was phosphate buffer pH=6.8, containing 8.8 mg/litre ofCTAB. The increase in absorbance corresponded to the release of Compoundof formula If. Composition 18. Tablet, 100 mg of Compound of formula IfTime % Released 5 min 18 10 min 44 15 min 59 30 min 83 60 min 100Experiments of Compositions Comprising More than One NO-Donating NSAID

Experiments were performed with compositions comprising Compound ofFormula Ig and Compound of Formula Ia, mixed with one or moresurfactant(s). Free-flowing powder comprising Compound of formula Ig wasmade by mixing the below mentioned composition P.

P. Compound of Formula Ig/Fujicalin™ 1/2

-   3 g Compound of formula Ig-   6 g Fujicalin™

A mixture of Compound of formula Ia and a surfactant was prepared bymelting and mixing the surfactant and the active drug with a pestle in amortar at 60° C.

Q. Compound of Formula Ia/Pluronic F87™ 1/0.3

-   3.08 g Compound of formula Ia-   0.92 g Pluronic F87™

Free-flowing powder comprising Compound of formula Ia was made by addingthe above mentioned mixture (Q) to porous particles, using a pestle in amortar at 60° C.

R. (Compound of Formula Ia/Pluronic F87™ 1/0.3)/Fujicalin 1/3

-   3 g Compound of formula Ia/Pluronic F87™ (Q)-   9 g Fujicalin™

The above mentioned mixtures were sieved through a 0.5 mm sieve andmixed with excipient mixture 2.

The compositions were compressed into tablets, weighing 1200 mg, using atablet machine rigged with 18 mm oval punches.

Composition 19:

Tablets, 120 mg of Compound of Formula Ig

-   3.60 g Compound of formula Ig/Fujicalin™ 1/2 (P)-   8.40 g Excipient mixture 2    Composition 20:    Tablets, 120 mg of Compound of Formula Ia-   6.24 g Compound of formula Ia/Pluronic F87™ (Q)-   5.76 g Excipient mixture 2    Composition 21:    Tablets, 120 mg of Compound of formula Ig and Compound of Formula Ia-   1.80 g Compound of formula Ig/Fujicalin™ (P)-   3.12 g Compound of formula Ia/Pluronic F87™ (Q)-   7.08 g Excipient mixture 2    Results—Composition 19 to 21

Dissolution tests were made using a thermostated beaker with a stirrer(150 rpm). The media used was phosphate buffer pH=6.8, containing 8.8mg/litre of CTAB. The increase in absorbance corresponded to the releaseof Compound of formula Ig and Compound of formula Ia. Composition 19:Tablet, 120 mg of Compound of formula Ig Time % Released 5 min 20 10 min37 15 min 44 30 min 78 60 min 100

Composition 20: Tablet, 120 mg of Compound of formula Ia Time % Released5 min 60 10 min 77 15 min 82 30 min 100 60 min 100

Composition 21: Tablet, 120 mg of Compound of formula Ig and Compound offormula Ia Time % Released 5 min 60 10 min 80 15 min 100 30 min 100 60min 100Experiments of Compositions Comprising a Combination of a NO-DonatingNSAID and a H⁺, K⁺-ATPase Inhibitor.

The following experiment show a composition comprising the Compound offormula Ia absorbed into a porous particle and mixed with enteric coatedpellets comprising an acid susceptible proton pump inhibitor.

Composition 22:

A solid drug delivery composition in the form of a tablet comprising 250mg of Compound of formula Ia and omeprazole 20 mg (as Mg-Omeprazole).

Enteric overcoated pellets comprising omeprazole and a powder of theporous particles comprising the Compound of formula Ia were manufacturedseparately, before compressing the two components together withpharmaceutically acceptable excipients into tablets.

Free-flowing powder of porous particles comprising Compound of formulaIa was made by making a mixture of Compound of formula Ia 250 parts byweight Calcium silicate 250 parts by weightin a mortar and working these drugs together. This mixture (500 parts byweight), a free-flowing powder, was sieved through a 0.5 mm sieve.

The enteric coated omeprazole pellet was made using the followingingredients: Core material (omeprazole) Magnesium omeprazole 15.00 kgNon-pareil seeds 15.00 kg Hydroxypropyl methylcellulose 2.25 kg Waterpurified 40 kg

Application of separating layer Core material (acc. to above) 15.00 kgHydroxypropyl cellulose 1.50 kg Talc 2.57 kg Magnesium Stearate 0.21 kgWater purified 20 kg

Enteric coating(omeprazole) Separating layered pellets (acc. to above)18.00 kg Methacrylic acid copolymer (30% suspension) 7.92 kg Triethylcitrate 2.38 kg Mono- and diglycerides (NF) 0.40 kg Polysorbate 80 0.04kg Water purified 17 kg

Over-coating(omeprazole) Enteric coated pellets 25.00 kg Hydroxypropylmethylcellulose 0.31 kg Mg-Stearate 0.009 kg Water purified 6 kg

The suspension layering was performed in a fluid bed apparatus.Magnesium omeprazole was sprayed onto inert non-pareil seeds from awater suspension containing the dissolved binder, i.e.hydroxypropylmethylcellulose.

The prepared core material was provided with a separating layer in afluid bed apparatus with a hydroxypropyl cellulose solution containingtalc and magnesium stearate. The enteric coating consisting ofmethacrylic acid copolymer, mono- and diglycerides, triethylcitrate andpolysorbate was sprayed onto the separating layered pellets in a fluidbed apparatus. In the same type of apparatus the enteric coated pelletswere coated with a hydroxypropyl methylcellulose/Mg-Stearate suspension.The over-coated pellets were sieved to remove possible agglomerates.Average medium particle size of the obtained pellets was around 0.5 mmin diameter.

The free-flowing powder comprising the porous particles comprisingCompound of formula Ia was (500 parts by weight) mixed with: Entericovercoated omeprazole pellets (from above) 100 parts by weightMicrocrystalline cellulose (Avicel pH 102 special coarse grade) 482parts by weight Polyvinyl pyrrolidone, cross-linked 16.5 parts by weightSodium stearylfumarate 1.5 parts by weight

Enteric overcoated omeprazole pellets were manufactured by chargingcomponents in proportions according to the recipe below;

The obtained mixture of porous particles comprising the absorbedCompound of formula Ia and the enteric coated pellets comprisingomeprazole was compressed in a tabletting machine to tablets having anaverage weight of 1095 mg, using 20 mm in diameter flat punches. Tablethardness was 5-6 kP.

Results—Composition 22

Omeprazole release was tested in USP dissolution apparatus No. 2(paddle), operated at 100 rpm. After preexposure to simulated gastricjuice for 2 hours the release was measured in 900 ml of phosphate bufferhaving a pH of 6.8, and after 30 minutes 90% of stated amount had beenreleased.

For the release of drug of formula Ia, the same kind of apparatus andmethod as above was used and operated at 100 rpm. As dissolution media1000 ml of phospahte buffer having a pH of 6.8 and also containing 8.8mg/ml of CTAB was used.

The release was followed spectrophotometrically at 269 nm. Theabsorbance increase corresponded to the following release of Compound offormula Ia. Composition 22, Tablet 250 mg of Compound of formula Ia Time% Released 30 min 36 60 min 77 90 min 86 120 min 92 180 min 99List of Abbreviations

-   USP United States Pharmacopeia-   CTAB cetyltrimethylammonium bromide

1. A solid drug delivery composition comprising one or more NO-donatingNon Steroidal Antiinflammatory Compound (s) (NO-donating NSAID(s))absorbed into porous particles.
 2. The solid drug delivery compositionaccording to claim 1 wherein one or more NO-donating NSAID(s) in oilyform is absorbed into porous particles.
 3. The solid drug deliverycomposition according to claim 1 wherein one or more NO-donatingNSAID(s) in melted form is absorbed into porous particles.
 4. The soliddrug delivery composition according to claim 1 wherein the porousparticles are selected from the group consisting of dibasic calciumphosphate, anhydrous, microcrystalline cellulose and pregelatinisedstarch or a mixture thereof.
 5. The solid drug delivery compositionaccording to claim 1 wherein the porous particles are spherical with aparticle size between 50 and 500 um.
 6. The solid drug deliverycomposition according to claim 5 wherein the particle size of thespherical porous particles is between 100 and 150 um.
 7. The solid drugdelivery composition according to claim 1 wherein the pore size of theporous particles is between 10 and 1000 Å.
 8. The solid drug deliverycomposition according to claim 7 wherein the pore size of the porousparticles is between 20 and 750 Å.
 9. The solid drug deliverycomposition according to claim 8 wherein the pore size of the porousparticles is between 50 and 500 Å.
 10. The solid drug deliverycomposition according to claim 1 wherein one or more NO-donatingNSAID(s) is absorbed together with one or more surfactant (s) into theporous particles.
 11. The solid drug delivery composition according toclaim 1 comprising a combinations of a) porous particles comprising anNO-donating NSAID and one or more surfactant(s) and b) porous particlescomprising an NO-donating NSAID without surfactant.
 12. The solid drugdelivery composition according to claim 10 wherein the NO-donatingNSAID(s) are the same.
 13. The solid drug delivery composition accordingto claim 10 wherein the surfactant (s) is non-ionic.
 14. The solid drugdelivery composition according to claim 13 wherein the surfactant(s) isa block co-polymer.
 15. The solid drug delivery composition according toclaim 13 wherein the surfactant(s) is a poloxamer.
 16. The solid drugdelivery composition according to claim 13 wherein the surfactant(s) isa polyoxyethylene polyoxybutylene block copolymer.
 17. The solid drugdelivery composition according to claim 10 wherein the ratio NO-donatingNSAID(s): surfactant(s) is within the range from 1:0.1 to 1:10 (w/w).18. The solid drug delivery composition according to claim 17 whereinthe ratio NO-donating NSAID(s): surfactant(s) is within the range from1:0.3 to 1:3 (w/w).
 19. The solid drug delivery composition according toclaim 1 wherein the NO-donating NSAID is an NO-donating naproxen. 20.The solid drug delivery composition according to claim 19 wherein theNO-donating naproxen is4-(nitrooxy)butyl-(S)-2-(9-methoxy-2-naphtyl)-propanoate.
 21. The soliddrug delivery composition according to claim 1 wherein the NO-donatingNSAID is an NO-donating diclofenac.
 22. The solid drug deliverycomposition according to claim 21 wherein the NO-donating diclofenac is2-[(2,6-dichlorophenyl)amino]benzeneacetic acid 4-(nitrooxy)-butylester.
 23. The solid drug delivery composition according to claim 21wherein the NO-donating diclofenac is 2-[2-(nitrooxy)ethoxy]ethyl{2-[(2,6-dichlorophenyl)amino]phenyl}acetate.
 24. The solid drugdelivery-composition according to claim 1 wherein the NO-donating NSAIDis an NO-donating ketoprofen.
 25. The solid drug delivery compositionaccording to claim 24 wherein the NO-donating ketoprofen is2-(3-benzoyl-phenyl)-propionic acid 3-nitrooxy-propyl ester or2-(3-benzoyl-phenyl)-propionic acid 4-nitrooxymethyl-benzyl ester. 26.The solid drug delivery composition according to claim 1 wherein theporous particles comprising an NO-donating NSAID, optionally mixed withone or more surfactant(s), are mixed together with enteric coatedpellets comprising a H+, K+-ATPase inhibitor.
 27. The solid drugdelivery composition according to claim 26 wherein the porous particlescomprising an NO-donating naproxen, an NO-donating diclofenac, anNO-donating ketoprofen or an NO-donating ketorolac, optionally mixedwith one or more surfactant(s), are mixed together with enteric coatedpellets comprising omeprazole, esomeprazole, lansoprazole, pantoprazoleor rabeprazole, leminoprazole or a pharmaceutical acceptable saltthereof.
 28. Process for producing the porous particles comprising oneor more NO-donating NSAID(s) according to claim 1 comprising mixing theNO-donating NSAID(s), optionally in oily or melted form, with porousparticles.
 29. Process for producing the porous particles comprising oneor more NO-donating NSAID(s) according to claim 1 comprising: a)dissolving the NO-donating NSAID(s) in one or more alcohol(s), b) addingthe porous particles during stirring, c) evaporating the addedalcohol(s), d) recovering the porous particles comprising theNO-donating NSAID(s), with a) and b) in optional order.
 30. Process forproducing the porous particles comprising one or more NO-donatingNSAID(s) according to claim 1 comprising: a) melting the NO-donatingNSAID(s), b) adding the porous particles, c) stirring the obtainedmixture, d) recovering the porous particles comprising the NO-donatingNSAID(s), with a) and b) in optional order.
 31. Process for producingporous particles comprising one or more NO-donating NSAID(s) and one ormore surfactant(s) according to claim 1 comprising: a) mixing theNO-donating NSAID(s) and the surfactant(s), b) adding the porousparticles, c) stirring the obtained mixture, d) recovering the porousparticles comprising the NO-donating NSAID(s) and the surfactant(s),with a) and b) in optional order.
 32. Process for producing the porousparticles comprising one or more NO-donating NSAID(s) and one or moresurfactant(s) according to claim 1 comprising: a) melting NO-donatingNSAID(s) and the surfactant(s), b) adding the porous particles, c)stirring the obtained mixture, d) recovering the porous particlescomprising NO-donating NSAID(s) and the surfactant(s), with a) and b) inoptional order.
 33. Process for producing the porous particlescomprising one or more NO-donating NSAID(s) according to claim 1comprising: a) mixing the NO-donating NSAID(s) and the porous excipient,b) adding water, stepwise, continuously, in one portion, c) extrudingthe obtained mixture into particles, d) spheronising the obtainedparticles, e) drying the obtained mixture, f) recovering the porousparticles comprising the NO-donating NSAID(s).
 34. The process accordingto claim 33 wherein the NO-donating NSAID(s) in step a) is pre-heated.35. The process according to claim 28 wherein the NO-donating NSAID(s)are the same.
 36. A solid drug delivery composition comprising one ormore NO-donating Non Steroidal Antiinflammatory Compound(s) (NO-donatingNSAID(s)) absorbed into porous particles wherein the porous particleshave been produced according to claim 28, are mixed withpharmaceutically acceptable excipients and compressed into a tablet. 37.A solid drug delivery composition comprising one or more NO-donating NonSteroidal Antiinflammatory Compound(s) (NO-donating NSAID(s)) absorbedinto porous particles wherein the porous particles have been producedaccording to claim 28, are filled into a capsule.
 38. The solid drugdelivery composition according to claim 36 wherein the capsules ortablets are coated.
 39. Use of the solid drug delivery compositionaccording to claim 1 for the manufacture of a medicament for treatingpain.
 40. Use of the solid drug delivery composition according to claim1 for the manufacture of a medicament for treating inflammation.
 41. Amethod for the treatment of pain comprising oral administration to apatient suffering therefrom a solid compound delivery compositionaccording to claim
 1. 42. A method for the treatment of inflammationcomprising oral administration to a patient suffering therefrom a solidcompound delivery composition according to claim 1.